Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (KontRASt-03)

• ClinicalTrials.gov Identifier: NCT05358249
• Recruitment Status: Recruiting
• First Posted: May 3, 2022
• Last Update Posted: February 9, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 27, 2022
• First Posted Date: May 3, 2022
• Last Update Posted Date: February 9, 2024
• Actual Study Start Date: October 24, 2022
• Estimated Primary Completion Date: May 5, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2022)

• Dose escalation: Incidence and severity of dose limiting toxicities (DLTs) of each combination treatment. [ Time Frame: 28 days ]
  A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value that is not primarily related to disease, disease progression, intercurrent illness/injury, or concomitant medications that occurs within the first 28 days of study treatment and meets a defined criteria.
• Dose escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment [ Time Frame: 24 months ]
  All information obtained on AE will be displayed by treatment group. Summary tables will include only AEs that started/worsened during the cycles of treatment (treatment-emergent AEs).
• Dose escalation: Frequency of dose interruptions and reductions, by treatment [ Time Frame: 24 months ]
  The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.
• Dose Escalation: Dose intensity by treatment [ Time Frame: 24 months ]
  Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.
• PhaseII: Overall Response Rate by Blinded Independent Review Committee (BIRC) per RECIST 1.1 [ Time Frame: 24 months ]
  ORR is the proportion of patients with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 27, 2022)

• Dose escalation and Phase II: ORR by local review per RECIST 1.1 [ Time Frame: 24 months ]
  ORR is the proportion of patients with a BOR of CR or PR.
• Dose escalation and Phase II: Disease Control Rate (DCR) by local review per RECIST 1.1 [ Time Frame: 24 months ]
  DCR is the proportion of patients with a BOR of CR or PR or Stable Disease (SD). The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
• Dose escalation and Phase II: Duration of Response (DoR) by local review per RECIST 1.1 [ Time Frame: 24 months ]
  Duration of response is defined as the time from the date of the first documented response (CR or PR), to the date of first documented progression, or death due any cause.
• Dose escalation and Phase II: Progression-Free Survival (PFS) by local review per RECIST 1.1 [ Time Frame: 24 months ]
  PFS is defined as the time from the date of start of treatment to the date of the first documented progression, or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
• Phase II: DCR by BIRC per RECIST 1.1 [ Time Frame: 24 months ]
  DCR is the proportion of patients with a BOR of CR or PR or SD. The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
• Phase II: DoR by BIRC per RECIST 1.1 [ Time Frame: 24 months ]
  Duration of response is defined as the time from the date of the first documented response (CR or PR), to the date of first documented progression, or death due any cause.
• Phase II: PFS by BIRC per RECIST 1.1 [ Time Frame: 24 months ]
  PFS is defined as the time from the date of start of treatment to the date of the first documented progression, or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
• Phase II: Overall survival (OS) [ Time Frame: 24 months ]
  OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.
• Dose escalation and Phase II: PK parameters - Maximum Concentration (Cmax), as applicable per arm [ Time Frame: 5 months ]
  The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1)
• Dose escalation and Phase II: PK parameters - Minimum Concentration (Cmin), as applicable per arm [ Time Frame: 5 months ]
  Observed concentration at the end of a dosing interval (taken directly before next administration)
• Dose escalation: Time to achieve Cmax - Tmax, as applicable per arm [ Time Frame: 5 months ]
  The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)
• Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCtau, as applicable per arm [ Time Frame: 5 months ]
  The Area under curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
• Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCinf, as applicable per arm [ Time Frame: 5 months ]
  The AUC from time zero to infinity (mass x time x volume-1)
• Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment [ Time Frame: 24 months ]
  All information obtained on AE will be displayed by treatment group. Summary tables will include only AEs that started/worsened during the cycles of treatment (treatment-emergent AEs).
• Phase II: Frequency of dose interruptions and reductions, by treatment [ Time Frame: 24 months ]
  The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.
• Phase II: Dose intensity by treatment [ Time Frame: 24 months ]
  Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation
• Official Title: KontRASt-03: A Phase Ib/II, Multicenter, Open-label Platform Study of JDQ443 With Select Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation
• Brief Summary: This is Phase Ib/II, multicenter, open-label adaptive platform study of JDQ443 with select therapies in patients with advanced solid tumors harboring the KRAS G12C mutation.
• Detailed Description: JDQ443 will be considered "backbone" treatment in this trial and combined with selected therapies, or "partner(s)". The combination of a backbone and a partner will constitute a treatment arm. After dose escalation, treatment arms that reach a maximum tolerated dose /recommended dose and are determined to be safe may, but are not required to, proceed to Phase II to further explore safety, tolerability, and anti-tumor activity.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• KRAS G12C Mutant Solid Tumors
• Carcinoma, Non-Small Cell Lung
• Carcinoma, Non-Small-Cell Lung
• Non-Small Cell Lung Cancer
• Non-Small Cell Lung Carcinoma
• Nonsmall Cell Lung Cancer
• Colorectal Cancer
• Colorectal Carcinoma
• Colorectal Neoplasms
• Colorectal Tumors
• Neoplasms, Colorectal

Intervention

• Drug: JDQ443
  KRAS G12C inhibitor, oral
• Drug: trametinib
  MEK inhibitor, oral
  Other Name: TMT212
• Drug: Ribociclib
  CDK4/6 inhibitor, oral
  Other Name: LEE011
• Biological: cetuximab
  EGFR inhibitor, intravenous

Study Arms

• Experimental: JDQ443+trametinib
  JDQ443 in combination with trametinib
  Interventions:

  • Drug: JDQ443
  • Drug: trametinib
• Experimental: JDQ443+ribociclib
  JDQ443 in combination with ribociclib
  Interventions:

  • Drug: JDQ443
  • Drug: Ribociclib
• Experimental: JDQ443+cetuximab
  JDQ443 in combination with cetuximab
  Interventions:

  • Drug: JDQ443
  • Biological: cetuximab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 18, 2022): 346
• Original Estimated Enrollment (submitted: April 27, 2022): 450
• Estimated Study Completion Date: June 16, 2027
• Estimated Primary Completion Date: May 5, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Dose Escalation:

- Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received standard of care therapy or are ineligible to receive such therapy.

Phase II:

• Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who have received platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant colorectal cancer who have received fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless patient was ineligible to such therapy.

All patients:

• ECOG performance status of 0 or 1.
• Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines.

Exclusion Criteria:

• Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations
• Prior treatment with a KRAS G12C inhibitor is excluded for patients in a subset of groups in Phase II.
• Active brain metastases, including symptomatic brain metastases or known leptomeningeal disease
• Clinically significant cardiac disease or risk factors at screening
• Insufficient bone marrow, hepatic or renal function at screening Other protocol-defined inclusion/exclusion criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

• Listed Location Countries: Belgium, France, Germany, Italy, Korea, Republic of, Singapore, Spain, United States

Administrative Information

• NCT Number: NCT05358249
• Other Study ID Numbers: CJDQ443E12101; 2021-006196-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: February 2024